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Open AccessArticle

Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
Department of Surgical Sciences, Eye Clinic, University of Turin, 10126 Turin, Italy
Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, F-75012 Paris, France
Univ. Lille, Inserm UMR-S 1172, CHU Lille, Biochemistry and Molecular Biology Department—UF Génopathies, F-59000 Lille, France
Fondation Ophtalmologique Adolphe de Rothschild, F-75019 Paris, France
Académie des Sciences-Institut de France, F-75006 Paris, France
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburg, PA 15213, USA
Institute of Ophthalmology, University College of London, London EC1V 9EL, UK
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(8), 2196;
Received: 21 May 2018 / Revised: 18 June 2018 / Accepted: 22 July 2018 / Published: 27 July 2018
(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters 2.0)
Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease. View Full-Text
Keywords: ABCA4; Stargardt disease; phenotype-genotype correlation ABCA4; Stargardt disease; phenotype-genotype correlation
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Nassisi, M.; Mohand-Saïd, S.; Dhaenens, C.-M.; Boyard, F.; Démontant, V.; Andrieu, C.; Antonio, A.; Condroyer, C.; Foussard, M.; Méjécase, C.; Eandi, C.M.; Sahel, J.-A.; Zeitz, C.; Audo, I. Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort. Int. J. Mol. Sci. 2018, 19, 2196.

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